Recently, substantial attention has been focused on the association between obesity and chronic inflammation. The aim of the present study was to investigate whether high-fat diet (HFD)-induced obesity induces the activation of the IL-1 type I receptor (IL-1RI)-mediated inflammatory signaling cascade in the skeletal muscle of mice. Male C57BL/6J mice were fed either an HFD or a normal diet (ND) for 12 wk. Compared with the results in mice receiving the ND, the HFD increased the expression of IL-1RI and downstream signaling proteins, such as myeloid differentiation primary response gene 88 (MyD88), IL-1R-associated kinase 4 and phospho-transforming growth factor-activated kinase 1 in the skeletal muscle. Additionally, activities of both inhibitor of kappaB kinase beta and inhibitor of kappaB degradation were significantly elevated in the skeletal muscle of mice fed with an HFD compared with mice receiving an ND. In contrast, the levels of other downstream transcription factors, such as activator protein-1 and INF regulatory factor 5, were not affected by the HFD. These results suggest that the IL-1RI-MyD88-nuclear factor kappaB signaling pathway might be involved in the induction of the inflammatory response in the skeletal muscle of mice fed with an HFD.